The lining of blood vessels, called the endothelium, is capable of secreting substances which allow blood vessels to relax in response to a variety of stimuli. One factor released is known as endothelium-derived-relaxant-factor (EDRF). Acetylcholine, a naturally occurring substance, is able to promote release of EDRF from blood vessels. Absence or dysfunction of the endothelium leads to diminished vasodilation or vasoconstriction with acetylcholine. Several previous studies have examined the effect of acetylcholine on large coronary arteries, but little information is available on the role of EDRF in the small blood vessels of the heart. We examined the importance of the dose of acetylcholine administered on the response of the small blood vessels of the heart. It is accepted that the response to acetylcholine of large coronary arteries in older patients and in patients with raised blood cholesterol level is diminished, but we found that the small blood vessel response to acetylcholine was not influenced significantly by age or the blood cholesterol level. We also examined the importance of the endothelium in patients who have chest pain and evidence of myocardial ischemia (angina) despite normal large coronary arteries, by investigating the effects of acetylcholine infusions on the reactivity of the small coronary arteries and comparing it with the response to another vasodilator, nitroprusside. Nitroprusside does not depend on an intact endothelium for its effect. This comparison revealed that a proportion of patients with chest pain despite normal large coronary arteries have dysfunction of their endothelium, with a diminished response to acetylcholine and a normal response to nitroprusside.